Processes for the alkylation of pyrazoles

ABSTRACT

The invention provides a process for the preparation of a compound of formula (I) in particular, wherein a compound of formula (II) is reacted with a dialkylsulphate. R 1  is C 1 -C 4 haloalkyl; R 2  is optionally substituted alkyl, optionally substituted aryl or optionally substituted heteroaryl; and R 3  is methyl or ethyl.

This application is a 371 of International Application No.PCT/EP2010/060884 filed Jul. 27, 2010, which claims priority to U.S.61/230,134 filed Jul. 31, 2009, and U.S. 61/361,570 filed Jul. 6, 2010,the contents of which are incorporated herein by reference.

The present invention relates to processes for the regioselectiveN-alkylation of substituted pyrazoles and to the use of alkylsulphonatesin the regioselective N-alkylation of substituted pyrazoles.

N-alkylated substituted pyrazoles, for example ethyl3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE), arevaluable intermediates in the preparation of fungicides, as described,for example, in WO 03/074491.

According to WO 95/25099, N-alkylated substituted pyrazoles can beprepared by reacting the corresponding substituted pyrazoles with alkylhalides under basic conditions. The use of alkyl halides in theN-alkylation of substituted pyrazoles is problematic, however, onaccount of their toxic properties. Furthermore, those compounds areexpensive and, in addition, exhibit only a low degree ofregioselectivity—in respect of the two nitrogen atoms of the pyrazolering. For those reasons, such processes are particularly unsuitable forlarge-scale preparation of N-alkylated substituted pyrazoles.

According to JP-2000-044541, N-alkylated substituted pyrazoles can beprepared by reacting the corresponding substituted pyrazoles withcarboxylic acid dialkyl esters, with addition of a base. The use ofcarboxylic acid dialkyl esters is not desirable, because those compoundsare of low reactivity. Furthermore, the regioselectivity of suchN-alkylation is generally dependent upon the chemical nature of thesubstituents on the pyrazole ring, so that N-alkylations usingcarboxylic acid dialkyl esters in some cases exhibit unsatisfactoryregioselectivity.

According to WO 2006/045504 N-alkylated substituted pyrazoles can beprepared regioselectively by reacting the corresponding substitutedpyrazoles with trialkyl phosphates.

There is a continuing need to find improved processes for preparing DFPEon a commercial scale which starts from easily and inexpensivelyobtainable starting materials.

The present invention relates to a process for the preparation ofcompounds of formula I:

-   wherein R¹ is C₁-C₄haloalkyl;-   R² is optionally substituted alkyl, optionally substituted aryl or    optionally substituted heteroaryl; and-   R³ is methyl or ethyl;-   wherein a compound of formula II:

-   wherein R¹ and R² are as defined for the compound of formula I;-   is reacted with a compound of formula III:

-   wherein R³ is as defined for the compound of formula I.

The alkyl groups appearing in the above substituent definitions may bestraight-chain or branched. For example an alkyl group may be methyl,ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl,preferably methyl or ethyl. Halogen is generally fluorine, chlorine,bromine or iodine, preferably fluorine. C₁-C₄ haloalkyl groups arederived from the mentioned C₁-C₄alkyl groups and are preferablydifluoromethyl or trifluoromethyl.

Aryl refers to aromatic hydrocarbon ring systems which may be a singlering or multiple rings which are fused together or linked covalently.Examples for aryl groups are phenyl, naphthyl, tetrahydronaphthyl,indanyl, indenyl, anthracenyl, phenanthrenyl and biphenyl.

Heteroaryl refers to aromatic ring systems comprising mono-, bi- ortricyclic systems wherein at least one oxygen, nitrogen or sulfur atomis present as a ring member. Examples are furyl, thienyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, benzothiophenyl,benzofuranyl, benzimidazolyl, indazolyl, benzotriazolyl, benzothiazolyl,benzoxazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl,quinazolinyl, cinnolinyl and naphthyridinyl.

R² may be optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl. This means that the alkyl, aryl andheteroaryl groups may or may not carry one or more identical ordifferent substituents. Normally not more than three substituents arepresent at the same time. Examples of substituents are: halogen, alkyl,haloalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, haloalkenyl,cycloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, cycloalkoxy,alkenyloxy, haloalkenyloxy, alkynyloxy, haloalkenyloxy, alkylthio,haloalkylthio, cycloalkylthio, alkenylthio, alkynylthio, alkylcarbonyl,haloalkylcarbonyl, cycloalkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl,alkoxyalkyl, cyano, nitro, hydroxy, mercapto, amino, alkylamino anddialkylamino.

Preferred optional substituents are C₁-C₈ alkyl, halo-C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₃-C₈cycloalkyl-C₁-C₈alkyl, C₂-C₈ alkenyl, halo-C₂-C₈alkenyl, C₃-C₈ cyclo-C₂-C₈ alkenyl, C₂-C₈ alkynyl, halo-C₂-C₈ alkynyl,C₁-C₈ alkoxy, halo-C₁-C₈ alkoxy, C₃-C₈ cycloalkoxy, C₂-C₈ alkenyloxy,halo-C₂-C₈ alkenyloxy, C₂-C₈ alkynyloxy, halo-C₂-C₈ alkenyloxy, C₁-C₈alkylthio, halo-C₁-C₈ alkylthio, C₃-C₈ cycloalkylthio, C₂-C₈alkenylthio, C₂-C₈ alkynylthio, C₁-C₈ alkylcarbonyl, halo-C₁-C₈alkylcarbonyl, C₃-C₈ cycloalkylcarbonyl, C₂-C₈ alkenylcarbonyl, C₂-C₈alkynylcarbonyl, C₁-C₈ alkoxy-C₁-C₈ alkyl, cyano, nitro, hydroxy,mercapto, amino, C₁-C₈ alkylamino and C₁-C₈ dialkylamino.

More preferred optional substituents are C₁-C₄ alkyl, halo-C₁-C₄ alkyl,C₃-C₆ cycloalkyl, C₃-C₆cycloalkyl-C₁-C₄alkyl, C₂-C₄ alkenyl, halo-C₂-C₄alkenyl, C₃-C₆ cyclo-C₂-C₄ alkenyl, C₂-C₄ alkynyl, halo-C₂-C₄ alkynyl,C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, C₃-C₆ cycloalkoxy, C₂-C₄ alkenyloxy,halo-C₂-C₄ alkenyloxy, C₂-C₄ alkynyloxy, halo-C₂-C₄ alkenyloxy, C₁-C₄alkylthio, halo-C₁-C₄ alkylthio, C₃-C₆ cycloalkylthio, C₂-C₄alkenylthio, C₂-C₄ alkynylthio, C₁-C₄ alkylcarbonyl, halo-C₁-C₄alkylcarbonyl, C₃-C₆ cycloalkylcarbonyl, C₂-C₄ alkenylcarbonyl, C₂-C₄alkynylcarbonyl, C₁-C₄ alkoxy-C₁-C₄ alkyl, cyano, nitro, hydroxy,mercapto, amino, C₁-C₄ alkylamino and C₁-C₄ dialkylamino.

Even more preferred optional substituents are C₁-C₄ alkyl, C₁-C₄haloalkyl, C₁-C₄ alkoxy, halo-C₁-C₄ alkoxy, halogen, hydroxy, cyano,nitro, and amino.

Typical examples for optionally substituted aryl include 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl,4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl,2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl,4-cyanophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 2-trifluoromethoxyphenyl,3-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,3-difluorophenyl,2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl,2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl,3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dibromophenyl,2,4-dibromophenyl, 2,5-dibromophenyl, 2,6-dibromophenyl,3,4-dibromophenyl, 3,5-dibromophenyl, 2,3-dimethylphenyl,2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,6-dimethylphenyl,3,4-dimethylphenyl, 3,5-dimethylphenyl, 2,3-dimethoxyphenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dicyanophenyl,2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl,3,4-dicyanophenyl, 3,5-dicyanophenyl, 2,3-bis(trifluoromethyl)phenyl,2,4-bis(trifluoromethyl)phenyl, 2,5-bis(trifluoromethyl)phenyl,2,6-bis(trifluoromethyl)phenyl, 3,4-bis(trifluoromethyl)phenyl,3,5-bis(trifluoromethyl)phenyl, 2,3-bis(trifluoromethoxy)phenyl,2,4-bis(trifluoromethoxy)phenyl, 2,5-bis(trifluoromethoxy)phenyl,2,6-bis(trifluoromethoxy)phenyl, 3,4-bis(trifluoromethoxy)phenyl,3,5-bis(trifluoromethoxy)phenyl, 2-chloro-5-fluorophenyl,2-fluoro-5-methylphenyl, 2-fluoro-5-methoxyphenyl,5-chloro-2-fluorophenyl, 2-chloro-5-methylphenyl,2-chloro-5-methoxyphenyl, 5-fluoro-2-methylphenyl,5-chloro-2-methylphenyl, 5-methoxy-2-methylphenyl,5-fluoro-2-methoxyphenyl, 5-chloro-2-methoxyphenyl and2-methoxy-5-methylphenyl.

Typical examples for optionally substituted heteroaryl include5-methyl-3-trifluoromethylpyrazol-1-yl,3-methyl-5-trifluoromethylpyrazol-1-yl,3,5-bis-trifluoromethylpyrazol-1-yl, 3,5-dimethylpyrazol-1-yl,5-ethyl-3-trifluoromethylpyrazol-1-yl,5-methyl-3-trifluoromethoxypyrazol-1-yl,2-methyl-4-trifluoromethylimidazol-1-yl,4-methyl-2-trifluoromethylimidazol-1-yl,2,4-bis-trifluoromethylimidazol-1-yl, 2,4-dimethylimidazol-1-yl,2-ethyl-4-trifluoromethylimidazol-1-yl,2-methyl-4-trifluoromethoxyimidazol-1-yl,5-methyl-3-trifluoromethyl[1,2,4]triazol-1-yl,3-methyl-5-trifluoromethyl[1,2,4]triazol-1-yl,3,5-bis-trifluoromethyl[1,2,4]triazol-1-yl and3,5-dimethyl[1,2,4]triazol-1-yl,5-ethyl-3-trifluoromethyl[1,2,4]triazol-1-yl,5-methyl-3-trifluoromethoxy[1,2,4]triazol-1-yl.

Alkoxy on its own or as part of another substituent is, depending uponthe number of carbon atoms mentioned, for example methoxy, ethoxy,1-propoxy, 2-propoxy, n-butoxy, 2-n-butoxy, or 2-tert-butoxy.

Alkenyl on its own or as part of another substituent is, depending uponthe number of carbon atoms mentioned, for example, ethenyl, allyl,propen-1-yl, buten-2-yl, buten-3-yl, penten-1-yl, penten-3-yl,hexen-1-yl or 4-methyl-penten-3-yl.

Alkynyl on its own or as part of another substituent is, depending uponthe number of carbon atoms mentioned, for example, ethynyl, propyn-1-yl,propyn-2-yl, butyn-1-yl, butyn-2-yl, 1-methyl-2-butynyl, hexyn-1-yl or1-ethyl-2-butynyl.

Preferably, R¹ is difluoromethyl or trifluoromethyl;

Preferably R² is C₁-C₈ alkyl, phenyl, or phenyl-C₁-C₈ alkyl, wherein thealkyl, phenyl and phenylalkyl are each optionally substituted with oneor more of, e.g. 1 to 3, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy,halo-C₁-C₄ alkoxy, halogen, hydroxy, cyano, nitro and amino. Morepreferably R² is C₁-C₈ alkyl or C₁-C₈ haloalkyl, phenyl or benzyl,wherein the phenyl and benzyl are each optionally substituted withhalogen, e.g. 1 to 3 halogen atoms. More preferably R² is C₁-C₆ alkyl.Even more preferably R² is C₁-C₄ alkyl. Most preferably R² is methyl orethyl.

Preferably R³ is methyl.

The process according to the invention is suitable preferably for thepreparation of compounds of formula I wherein R¹ is C₁-C₄haloalkyl; R²is C₁-C₆ alkyl; and R³ is methyl or ethyl.

In particular, the process according to the invention is suitablepreferably for the preparation of compounds of formula I wherein R¹ isdifluoromethyl or trifluoromethyl; R² is methyl or ethyl; and R³ ismethyl.

The process according to the invention is especially suitable for thepreparation of compounds of formula I wherein R¹ is difluoromethyl.

The process according to the invention is very especially suitable forthe preparation of compounds of formula I wherein R¹ is difluoromethyl;R² is ethyl and R³ is methyl.

Preferably the compound of formula III is dimethyl sulphate.

Preferably the reaction is carried out in a biphasic solvent system, inparticular a liquid-liquid biphasic solvent system, e.g. one comprisingwater and a water-immiscible organic solvent. The term“water-immiscible” means that when the organic solvent is mixed withwater under the conditions of the process according to the invention twoseparate liquid phases are formed. Suitable organic solvents areoptionally halogenated aromatic hydrocarbon solvents, ketone solvents,optionally halogenated hydrocarbon solvents or ether solvents. In saiddefinitions, halogen is generally fluorine, chlorine, bromine and/oriodine, preferably fluorine, bromine and/or chlorine. Preferred solventsare aromatic-based organic solvents, e.g. those containing a phenylgroup, and/or ethers. Preferred examples are toluene, xylene,mesitylene, tert-butyl benzene, chlorobenzene, 1,2-dichlorobenzene,decalin, dibutyl ether, dipentyl ether, diphenyl ether and anisole. Insome cases, more than one type of solvent may be employed. A mixture oftoluene and water or xylene and water is preferably employed as solvent.

When the reaction is performed using a one-phase solvent system, thesolvent is preferably an organic solvent as described above, withtoluene and xylene, particularly toluene, being preferred.

Preferably the process is performed using a phase transfer catalyst.Suitable phase-transfer catalysts are quaternary phosphonium salts suchas, for instance, (alkyl)₄P⁺Hal⁻, (aryl)₄P⁺Hal⁻, alkylaryl-P⁺Hal⁻, etc.(Hal referring to halide) or quanternary ammonium salts such as, forinstance, tetraalkylammonium halides or hydroxides, tetraarylammoniumhalides or hydroxides, alkylarylammonium halides or hydroxides, etc.,which are described for example in C. M. Starks, C. L. Liotta, M. C.Halpern, Phase Transfer Catalysis; Chapman & Hall; New York, 1994.

Preferably, the phase transfer catalyst is selected from1,4-diazabicyclo[2,2,2]octane (DABCO), tetramethylammonium chloride(TMAC), tricaprylylmethylammonium chloride (Aliquat 336®),tetrabutylammonium chloride (TBAC), tetrabutylammonium bromide (TBAB)and triphenylphosphonium chloride (TPPC).

The phase transfer catalyst is generally employed in the inventivereaction in an amount of from 0.001 to 0.1 mol per mol of compound offormula I. An amount of from 0.01 to 0.05 mol per mol of compounds offormula I is preferred.

Preferably the process is performed in the presence of a base. The basemay be any suitable base. Suitable bases are, for example, hydroxidesand carbonates, e.g. alkali hydroxides and alkali carbonates. Preferredexamples are for instance, sodium hydroxide, potassium hydroxide, etc.or alkali carbonate, for instance, sodium carbonate, potassiumcarbonate, etc. Sodium hydroxide is preferably employed as the base. Thebase is preferably provided in an amount such that the pH is 9 to13,preferably 9.5 to 12.5 more preferably 10.5 to 12, most preferably 10.8to 11.5.

The reaction according to the invention is preferably carried out in atemperature range of from 0° C. to 100° C., preferably 10° C. to 50° C.,especially from 15° C. to 50° C.

In the reactions according to the invention, compounds of formula IIIare usually used in equimolar amounts or in excess relative to compoundsof formula II, preferably in an up to 10-fold molar excess, especiallyin an up to 5-fold molar excess, more especially in an equimolar to2-fold molar excess, even more especially in an equimolar to 1.5 molarexcess. Most preferred is a slight molar excess of compound of formulaIII relative to the compounds of formula II, e.g. from more thanequimolar to 1.4 molar excess, e.g. 1.05 to 1.3 molar excess.

The process according to the invention is very especially suitable forthe preparation of compounds of formula I wherein R¹ is difluoromethyl,R² is ethyl and R³ is methyl, by reaction of a compound of formula IIwherein R¹ is difluoromethyl and R² is ethyl with a compound of formulaIII wherein R³ is methyl, in a biphasic solvent system, in the presenceof base and phase transfer catalyst.

In particular, the process according to the invention is very especiallysuitable for the preparation of compounds of formula I wherein R¹ isdifluoromethyl, R² is ethyl and R³ is methyl, by reaction of a compoundof formula II wherein R¹ is difluoromethyl and R² is ethyl with acompound of formula III wherein R³ is methyl, in a temperature range offrom 0° C. to 100° C., in a biphasic solvent system, in the presence ofbase and phase transfer catalyst, the compound of formula III being usedin an equimolar to 2-fold excess relative to the compound of formula II.

The compounds of formula II are known or can be prepared analogously toprocesses known in the literature. For example, such compounds can beprepared from the 3-oxo-carboxylic acid esters on which they are basedby means of a two-step synthesis by reaction with trimethyl orthoformateand subsequent reaction with hydrazine. Such reactions are described,for example, in JP-2000-044541. A further synthesis route for thepreparation of compounds of formula II is described in JP-2001-322983,wherein, for example, ethyl 3-trifluoromethylpyrazole-4-carboxylate isprepared starting from ethyl3-chloro-4,4,4-trifluoro-2-formyl-2-butenoic acid ester by reaction withhydrazine. Compounds of formula III are commercially available.

The present invention relates also to the use of compounds of formulaIII in the regioselective alkylation of compounds of formula II. Thepresent invention relates also to a process for the regioselectivealkylation of compounds of formula II, wherein a compound of formula IIIis used as alkylating agent.

Table 1 shows examples of compounds of formula I of the invention.

TABLE 1 Compounds of formula I: (I)

Comp. No. R₁ R₂ R₃ A1 CF₂H CH₂CH₃ CH₃ A2 CF₂H CH₃ CH₃ A3 CF₂H CH₃ CH₂CH₃A4 CF₂H CH₂CH₃ CH₂CH₃ A5 CF₃ CH₂CH₃ CH₃ A6 CF₃ CH₃ CH₃ A7 CF₃ CH₃ CH₂CH₃A8 CF₃ CH₂CH₃ CH₂CH₃

The present invention makes it possible for substituted pyrazoles to bealkylated in a controlled manner in a high yield, with a high degree ofregioselectivity and at low cost.

A further advantage of the present invention is that the desired productethyl 3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE) canbe purified by sequential vacuum distillation, first to remove undesiredethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE),then DFPE. It can also be purified by crystallization.

Accordingly, the process may include the step of separating bydistillation the compound of formula I from any compound of formula IV:

-   wherein R¹, R² and R³ are as defined above;    that has formed in the process.

The process may comprise purifying the compound of formula I, e.g. bycrystallisation.

The starting materials for the process of the present invention aredistinguished by ready accessibility and ease of handling and are alsoinexpensive.

In a further aspect the invention provides a process for the preparationof compounds of formula I:

-   wherein R¹ is C₁-C₄haloalkyl;-   R² is optionally substituted alkyl, optionally substituted aryl or    optionally substituted heteroaryl; and-   R³ is methyl or ethyl;-   comprising-   a) reacting a compound of formula V:

-   wherein R¹ and R² are as defined for the compound of formula I and    R⁴ is hydrogen, optionally substituted alkyl, optionally substituted    aryl or optionally substituted heteroaryl;-   with hydrazine in the presence of water and a water-immiscible    organic solvent to form a compound of formula II:

-   wherein R¹ and R² are as defined for the compound of formula I; and-   b) reacting the compound of formula II with an alkylating agent in    situ to produce the compound of formula I.

Preferred definitions of R¹, R², R³ are the same as those given above.Most preferably R¹ is difluoromethyl, R² is C₁-C₆ alkyl e.g. ethyl, R⁴is hydrogen or C₁-C₆ alkyl, more preferably C₁-C₆ alkyl, e.g. ethyl, andR³ is methyl.

For example, reacting the compound of formula II with an alkylatingagent in situ means that the compound of formula II is not isolated fromthe crude reaction mixture prior to reaction with the alkylating agent.Accordingly, the preparation of a compound of formula I from thecompound of formula II may be a “one-pot” reaction, e.g. step b) may beperformed after step a) in the same vessel. This simplifies the plantrequirements for the process.

Following the reaction of the compound of formula V with hydrazine, theorganic phase will contain the compound of formula I. The organic phasemay be separated from the aqueous phase prior to reacting the compoundof formula II with an alklyating agent. The alkylating agent may then beadded to the organic phase. The alkylation reaction may also beperformed using a biphasic solvent system.

The alkylating agent may be selected from known alkylating agents.Suitable alkylating agents may include for example alkyl phosphates,alkyl phosphonates, an alkyl phosphites, alkyl sulphates and alkylcarbonates, for example a compound of formula III, VI, VII or VIII:

wherein

-   R³ is methyl or ethyl;-   R⁵ is hydrogen, optionally substituted alkyl, optionally substituted    aryl or optionally substituted heteroaryl, preferably hydrogen or    C₁-C₆ alkyl, e.g. ethyl; and-   n is 0 or 1.

Preferred alkylating reagents are compounds of formula III and VI,particularly alkylphosphates and alkylsulphonates. Dimethylsulphate andtrimethylphosphate are particularly preferred.

In step a) hydrazine can be used in equimolar amounts, in sub-equimolaramounts or in excess relative to compounds of formula V, preferablyhydrazine is used in slight excess relative to compounds of formula V.Thus the molar ratio of hydrazine:compound of formula V is preferablyfrom 1:0.8 to 1:1.2, preferably 1:1.1. Hydrazine may be used in the formof an aqueous solution.

Preferred organic solvents in step a) are as described above foralkylation of compounds of formula II with compounds of formula III.

Process step a) is preferably carried out in a temperature range from−20° C. to 50° C., preferably from 0° C. to 50° C., especially from 5°C. to 25° C.

The reaction time for process step a) is generally from 15 minutes to 48hours, preferably 15 minutes to 18 hours, more preferably 15 minutes to5 hours or from 1 to 5 hours. Said step can be carried out at normal,elevated or reduced pressure. In one embodiment, said step is carriedout at normal pressure.

An example of step a) is a process step comprising: preparing a solutioncomprising hydrazine or hydrazine hydrate and an organic solvent,preparing a suspension/solution of the compound of formula V in theorganic solvent, and mixing the solution and the suspension or bothsolutions. The solution comprising hydrazine can be added to thesuspension/solution of the compound of formula V in the organic solventor vice versa. In one embodiment, the suspension/solution of thecompound of formula V in the organic solvent is added to the solutioncomprising hydrazine.

Step b) may be performed under similar conditions as described above forthe reaction of compounds of formula II with compounds of formula III.Preferably step b) is performed according using a compound of formulaIII according to the invention as described above.

Compounds of formula V occur in two isomers with regard to the doublebond substituted by the alkoxy group —O—R₂: the E- and the Z-isomer.Both isomers or mixtures thereof can be used in the processes accordingto the invention.

Compounds of formula V are described for example in WO 2008/113447.

In a further aspect the invention provides a process for the preparationof a compound of formula I:

-   wherein R¹ is C₁-C₄haloalkyl;-   R² is optionally substituted alkyl, optionally substituted aryl or    optionally substituted heteroaryl; and-   R³ is methyl or ethyl;-   wherein a compound of formula II:

-   wherein R¹ and R² are as defined for the compound of formula I;    is reacted with an alkylating agent in a liquid-liquid biphasic    solvent system.

Preferably the biphasic solvent system is water and a water-immiscibleorganic solvent, e.g. as described above.

The alkylating agent may be selected from known alkylating agents.Suitable alkylating agents may include for example alkyl phosphates,alkyl phosphonates, an alkyl phosphites, alkyl sulphates and alkylcarbonates, for example a compound of formula III, VI, VII or VIII:

wherein

-   R³ is methyl or ethyl;-   R⁵ is hydrogen, optionally substituted alkyl, optionally substituted    aryl or optionally substituted heteroaryl, preferably hydrogen or    C₁-C₆ alkyl, e.g. ethyl; and-   n is 0 or 1.

Preferably the alkylating agent is a compound of formula III, VI or VII,more preferably a compound of formula III. More preferred alkylatingreagents are compounds of formula III and VI, particularlyalkylphosphates and alkylsulphonates. Dimethylsulphate andtrimethylphosphate are particularly preferred.

In a further aspect the invention provides a process for the preparationof a compound of formula IX:

-   wherein R¹ is C₁-C₄haloalkyl and R³ is methyl or ethyl;    comprising hydrolysing a compound of formula I, prepared as    described above.

Hydrolysis of the compound of formula I may be achieved by performingthe steps:

-   i) saponifying that compound in situ leading to the formation of a    compound of formula IX by-   ii) adding a base to form the anion of the compound of formula IX;-   ii′) adding an acid to form the compound of formula IX;    e.g. as described in WO 2008/145257.

In a further aspect the invention provides a process for the preparationof a compound of formula X:

-   wherein R¹ is C₁-C₄haloalkyl and R³ is methyl or ethyl;-   A is thienyl, phenyl, or ethylene each optionally substituted by one    to three groups independently selected from halogen, methyl and    methoxy,-   B is a direct bond, cyclopropylene, an annelated    bicyclo[2.2.1]heptane- or bicyclo[2.2.1]heptene ring,-   D is hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy,    C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₁-C₆ alkylidene, C₁-C₆    haloalkylidene, phenyl or phenyl optionally substituted by one to    three substituents independently selected from halogen and    trihalomethylthio;-   comprising providing a compound of formula IX:

-   wherein R¹ is C₁-C₄haloalkyl and R³ is methyl or ethyl; according to    the processes described above; and-   reacting the compound of formula IX or the corresponding acid-halide    with a compound of formula XI:    H₂N-A-B-D   (XI)    wherein A, B and D are as defined for the compound of formula X.

The compound of formula X is preferably a compound of formula XII(Isopyrazam), a compound of formula XIII (Sedaxane), a compound offormula XIV, a compound of formula XV (Penthiopyrad), a compound offormula XVI (Bixafen), a compound of formula XVII (Fluxapyroxad), acompound of formula XVIII, or a compound of formula XIX:

The step of reacting the compound of formula IX or the correspondingacid-halide with a compound of formula XI may be performed according toknown methods, e.g. as described in WO 2004/035589 or WO 2009/135860.For example, the compound of formula I may be treated with ahalogenating agent, such as thionyl chloride, oxalyl chloride, phosgene,SF₄, DAST, deoxofluor or thionylbromide to provide the acid-halogen,e.g. the acid chloride, which may then be reacted with the compound offormula XI in the presence of a suitable base, e.g. LiOH, KOH, NaOH,NEt₃, NaHCO₃, KHCO₃, Na₂CO₃ or K₂CO₃, e.g. in a solvent such as toluene,xylenes, dichloromethane, ethyl acetate or DMF, e.g. at −10° C. to 30°C.

Isopyrazam, Sedaxane, Penthiopyrad, Fluxapyroxad and Bixafen are knownfungicides. The compound of formula XIV is known, e.g. from WO2007/048556, the compound of formula XVIII is known e.g. from WO2010/000612, the compound of formula XIX is known e.g. from WO2008/053044.

EXAMPLES Example 1 Preparation of ethyl3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE) Using aBiphasic Solvent System Example 1a

19 g (0.10 mol) of ethyl 3-difluoromethylpyrazole-4-carboxylate, toluene(60 ml), water (70 ml), and tetramethylammonium chloride (0.2 g) weremixed. 4.6 g of 25% aqueous sodium hydroxide (0.03 mol) was added whilestirring. The mixture was cooled to 15° C. Then, over the course of 2hours, 15.1 g of dimethyl sulphate (0.12 mol) and 11.2 g of additionalsodium hydroxide (0.07 mol) were fed simultaneously while maintainingthe pH at 10.8 to 11.0 and pot temperature at 15° C. The reactionmixture was allowed to stir at the same temperature while maintainingthe pH at 10.8-11.0 by feeding additional sodium hydroxide solution. Thebottom aqueous phase was separated off. The organic phase wasconcentrated in vacuo to give 20.0 g of crude product as a 70:30 mixtureof DFPE and ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate(iso-DFPE).

The desired DFPE product was purified by vacuum distillation at 95° C./5mbar to remove undesired iso-DFPE, followed by recrystallization inmethanol-water. 11.8 g (99.9%, 0.06 mol) of DFPE was obtained. DFPE canalso be isolated and purified by vacuum distillation at 110° C./1 mbar.

Example 1b

19 g (0.10 mol) of ethyl 3-difluoromethylpyrazole-4-carboxylate, toluene(60 ml), water 30 (35 ml), and tetrabutylammonium bromide (0.2 g) weremixed. 4.6 g of 25% aqueous sodium hydroxide (0.03 mol) was added whilestirring. The mixture was cooled to 15° C. Then, over the course of 2hours, 15.1 g of dimethyl sulphate (0.12 mol) and 11.2 g of additionalsodium hydroxide (0.07 mol) were fed simultaneously while maintainingthe pH at 10.8 to 11.0 and pot temperature at 15° C. The reactionmixture was allowed to stir at the same temperature while maintainingthe pH at 10.8-11.0 by feeding additional sodium hydroxide solution. Thebottom aqueous phase was separated off. GC analysis of the organic phaseshowed that it contains 20.0 g of crude product as a 70:30 mixture ofDFPE and ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate(iso-DFPE). The combined yield is 95%.

Example 1c

63.8 g (0.336 mol) of ethyl 3-difluoromethylpyrazole-4-carboxylate,toluene (260 ml), and water (52 ml) were mixed. 18.0 g of 25% aqueoussodium hydroxide (0.112 mol) was added while stirring. Then, over thecourse of 2 hours, 49.6 g of dimethyl sulphate (0.390 mol) and 45.3 g ofadditional sodium hydroxide (0.283 mol) were fed simultaneously whilemaintaining the pH at 11.3 to 11.6 and pot temperature at 25° C. Thereaction mixture was allowed to stir at the same temperature for 2 hourswhile maintaining the pH at 11.3-11.6 by feeding additional sodiumhydroxide solution. The bottom aqueous phase was separated off. GCanalysis of the organic phase showed that it contains 64.5 g of crudeproduct as a 62:38 mixture of DFPE and ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE). Thecombined yield is 94%.

Example 2 Preparation of ethyl3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE) Using aMonophasic Solvent System Example 2a

31.9 g (0.17 mol) of ethyl 3-difluoromethylpyrazole-4-carboxylate,toluene (110 ml), 34.8 g of potassium carbonate (0.5 mol) andtetramethylammonium chloride (1.2 g) were mixed. Then, over the courseof 2 hours, 26.4 g of dimethyl sulphate (0.21 mol) was fed whilemaintaining the pot temperature at 25° C. The reaction mixture wasallowed to stir at the same temperature for additional 2 hours. Water(200 g) was added to dissolve the solid by-products. The bottom aqueousphase was separated off. GC analysis of the organic phase showed that itcontains 32.3 g of crude product as a 58:42 mixture of DFPE and ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE). Thecombined yield is 95%.

Example 2b

31.9 g (0.17 mol) of ethyl 3-difluoromethylpyrazole-4-carboxylate,toluene (110 ml) and 34.8 g of potassium carbonate (0.5 mol) were mixed.Then, over the course of 2 hours, 26.4 g of dimethyl sulphate (0.21 mol)was fed while maintaining the pot temperature at 25° C. The reactionmixture was allowed to stir at the same temperature for additional 2hours. Water (200 g) was added to dissolve the solid by-products. Thebottom aqueous phase was separated off. GC analysis of the organic phaseshowed that it contains 32.2 g of crude product as a 58:42 mixture ofDFPE and ethyl 5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate(iso-DFPE). The combined yield is 95%.

Example 3 One-Pot Preparation of ethyl3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (DFPE)

A mixture of toluene (450 ml) and hydrazine monohydrate (48.8 g, 0.98mol) was stirred at 15-20° C.2-[1-Ethoxy-meth-(Z)-ylidene]-4,4-difluoro-3-oxo-butyric acid ethylester (175.3 g, 91.5% strength, 0.72 mol) was fed over 2 hours via asyringe pump while maintaining the temperature at 15-20° C. The reactionmass was held at 15-20° C. for additional 30 minutes to complete thereaction.

The reaction mixture was then warmed to 30° C. to dissolve the solidproduct. The bottom aqueous phase was decanted off. The organic phasewas washed with 2% HCl (50 ml) to remove residual hydrazine. The twoaqueous phases were combined and extracted with toluene (50 ml). Thetoluene extract contains additional 3-4% yield of ethyl3-difluoromethylpyrazole-4-carboxylate and was combined with the productsolution.

The toluene solution of crude ethyl3-difluoromethylpyrazole-4-carboxylate was stirred and cooled to 20° C.Water (260 ml), tetramethylammonium chloride (10% aqueous solution, 15.0g), and 25% NaOH solution (36-60 g) were added in sequence. Dimethylsulphate (99.5%, 94.5 g, 0.75 mol) and additional 25% NaOH were fedsimultaneously over 2 hours at 20° C. while maintaining the pH between10.5 and 12.0. After 2 hours post reaction, the bottom aqueous phase wasseparated off.

After solvent was evaporated off, the crude reaction mass was vacuumdistilled to afford 46.5 g of ethyl5-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylate (iso-DFPE) as adistillation fraction. The distillation residue contains 86.3 g of DFPEand less than 1.0 g of iso-DFPE, and can be hydrolyzed directly toproduce the corresponding acid.

What is claimed is:
 1. A process for the preparation of a compound offormula I:

wherein R¹ is C₁-C₄haloalkyl; R² is optionally substituted alkyl,optionally substituted aryl or optionally substituted heteroaryl; and R³is methyl or ethyl; wherein a compound of formula II:

wherein R¹ and R² are as defined for the compound of formula I; isreacted with a compound of formula III:

wherein R³ is as defined for the compound of formula I.
 2. A processaccording to claim 1, wherein the reaction is performed in aliquid-liquid biphasic solvent system.
 3. A process according to claim2, wherein the biphasic solvent system comprises water and awater-immiscible organic solvent.
 4. A process according to claim 2,wherein the reaction is performed in the presence of a phase transfercatalyst.
 5. A process according to claim 4, wherein the phase transfercatalyst is a quaternary phosphonium salt or a quanternary ammoniumsalt.
 6. A process according to claim 4, wherein the phase transfercatalyst is selected from 1,4-diazabicyclo[2,2,2]octane (DABCO),tetramethylammonium chloride (TMAC), tricaprylylmethylammonium chloride(Aliquat 336®), tetrabutylammonium chloride (TBAC), tetrabutylammoniumbromide (TBAB) and triphenylphosphonium chloride (TPPC).
 7. A processaccording to claim 1 wherein the compound of formula III is present inan amount which is equimolar to 2-fold molar excess relative to thecompound of formula II.
 8. A process according to claim 1, wherein thereaction is carried out in the presence of a base.
 9. A processaccording to claim 8, wherein the base is a hydroxide or a carbonate.10. A process according to claim 1, wherein the process comprises thestep of separating by distillation the compound of formula I from anycompound of formula IV:

wherein R¹, R² and R³ are as defined for the compound of formula I inclaim 1; that has formed in the process according to claim
 1. 11. Aprocess according to claim 1, wherein R² is C₁-C₆ alkyl.
 12. A processfor the regioselective alkylation of a compound of formula II:

wherein R¹ is C₁-C₄haloalkyl; and R² is optionally substituted alkyl,optionally substituted aryl or optionally substituted heteroaryl;wherein a compound of formula III:

wherein R³ is methyl or ethyl; is used as the alkylating agent.
 13. Aprocess for the preparation of a compound of formula I:

wherein R¹ is C₁-C₄haloalkyl; R² is optionally substituted alkyl,optionally substituted aryl or optionally substituted heteroaryl; and R³is methyl or ethyl; comprising a) reacting a compound of formula V:

wherein R¹ and R² are as defined for the compound of formula I and R⁴ ishydrogen, optionally substituted alkyl, optionally substituted aryl oroptionally substituted heteroaryl; with hydrazine in the presence ofwater and a water-immiscible organic solvent to form a compound offormula II:

wherein R¹ and R² are as defined for the compound of formula I; and b)reacting the compound of formula II with an alkylating agent in situ toproduce the compound of formula I, wherein the alkylating agent is acompound of formula (III)

wherein R³ is methyl or ethyl.
 14. A process according to claim 13,wherein after step a) the organic phase is separated from the aqueousphase prior to reacting the compound of formula II with an alklyatingagent in step b).
 15. A process according to claim 13, wherein thewater-immiscible organic solvent is an aromatic-based solvent and/or anether.
 16. A process according to claim 13, wherein the alkylating agentis selected from dimethylsulphate and trimethylphosphate.
 17. A processfor the preparation of a compound of formula I:

wherein R¹ is C₁-C₄haloalkyl; R² is optionally substituted alkyl,optionally substituted aryl or optionally substituted heteroaryl; and R³is methyl or ethyl; wherein a compound of formula II:

wherein R¹ and R² are as defined for the compound of formula I; isreacted with an alkylating agent in a liquid-liquid biphasic solventsystem, wherein the alkylating agent is a compound of formula (III)

wherein R³ is methyl or ethyl.
 18. A process according to claim 17,wherein the biphasic solvent system comprises water and awater-immiscible organic solvent.
 19. A process according to claim 17,wherein the alkylating agent is selected from dimethylsulphate andtrimethylphosphate.
 20. A process for the preparation of a compound offormula IX:

wherein R¹ is C₁-C₄haloalkyl and R³ is methyl or ethyl; comprisinghydrolysing a compound of formula I, prepared according to a method asdefined in claim
 1. 21. A process for the preparation of a compound offormula X:

wherein R¹ is C₁-C₄haloalkyl; R³ is methyl or ethyl; A is thienyl,phenyl, or ethylene each optionally substituted by one to three groupsindependently selected from halogen, methyl and methoxy, B is a directbond, cyclopropylene, an annelated bicyclo[2.2.1]heptane- orbicyclo[2.2.1]heptene ring, D is hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆haloalkyl, C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₃-C₆ cycloalkyl, C₁-C₆alkylidene, C₁-C₆ haloalkylidene, phenyl or phenyl optionallysubstituted by one to three substituents independently selected fromhalogen and trihalomethylthio; comprising providing a compound offormula IX:

wherein R¹ is C₁-C₄haloalkyl and R³ is methyl or ethyl; according to theprocess as defined in claim 20; and reacting the compound of formula IXor the corresponding acid-halide with a compound of formula XI:H₂N-A-B-D  (XI) wherein A, B and D are as defined for the compound offormula X.
 22. A process according to claim 21, wherein the compound offormula X is a compound of formula XII (Isopyrazam), a compound offormula XIII (Sedaxane), a compound of formula XIV, a compound offormula XV (Penthiopyrad), a compound of formula XVI (Bixafen), acompound of formula XVII (Fluxapyroxad), a compound of formula XVIII, ora compound of formula XIX: